A Longitudinal, Observational Study of Etiology and Long-Term Outcomes of Sepsis in Malawi Revealing the Key Role of Disseminated Tuberculosis

Abstract

Background: Sepsis protocols in sub-Saharan Africa are typically extrapolated from high-income settings, yet sepsis in sub-Saharan Africa is likely caused by distinct pathogens and may require novel treatment strategies. Data to guide such strategies are lacking. We aimed to define causes and modifiable factors associated with sepsis outcomes in Blantyre, Malawi, in order to inform the design of treatment strategies tailored to sub-Saharan Africa.

Methods: We recruited 225 adults who met a sepsis case definition defined by fever and organ dysfunction in an observational cohort study at a single tertiary center. Etiology was defined using culture, antigen detection, serology, and polymerase chain reaction. The effect of treatment on 28-day outcomes was assessed using Bayesian logistic regression.

Results: There were 143 of 213 (67%) participants living with human immunodeficiency virus (HIV). We identified a diagnosis in 145 of 225 (64%) participants, most commonly tuberculosis (TB; 34%) followed by invasive bacterial infections (17%), arboviral infections (13%), and malaria (9%). TB was associated with HIV infection, whereas malaria and arboviruses with the absence of HIV infection. Antituberculous chemotherapy was associated with survival (adjusted odds ratio for 28-day death, 0.17; 95% credible interval, 0.05-0.49 for receipt of antituberculous therapy). Of those with confirmed etiology, 83% received the broad-spectrum antibacterial ceftriaxone, but it would be expected to be active in only 24%.

Conclusions: Sepsis in Blantyre, Malawi, is caused by a range of pathogens; the majority are not susceptible to the broad-spectrum antibacterials that most patients receive. HIV status is a key determinant of etiology. Novel antimicrobial strategies for sepsis tailored to sub-Saharan Africa, including consideration of empiric antituberculous therapy in individuals living with HIV, should be developed and trialed.

Keywords: Africa south of the Sahara; HIV; antimicrobial resistance; critical illness; tuberculosis.

Figure 1.

UpSet plot of diagnoses. Black circles in the lower half of the plot show diagnoses: either a single diagnosis (single circle) or 2 or more diagnoses (black circles linked by lines), with the large bar chart (top right) showing the number of participants with the indicated diagnosis or diagnoses. Only participants who had a diagnosis are included in this plot. The 5 most frequent diagnoses are shown, demonstrating that most participants had only 1 diagnosis. Red bar indicates receipt of antibacterial therapy, showing that almost all participants received antibacterial therapy despite no demonstrated invasive bacterial infection in many cases.

Figure 2.

Kaplan-Meier estimate of survival function following sepsis admission, stratified by HIV status. Abbreviations: CrI, credible interval; HIV, human immunodeficiency virus; HR, hazard ratio.

Figure 3.

Determinants of sepsis mortality. A, Host severity PC1 and PC2 showing that PC1 defines an axis of HIV, immunosuppression (low CD4 count and anemia), and shock (tachycardia, low blood pressure, and bicarbonate), whereas PC2 is associated with sepsis-related organ dysfunction, age, and male sex. B, Participants projected onto PC1 and PC2 showing that participants who die (circles) tend to have immunosuppression and shock (upper right), other sepsis-related organ dysfunction (lower left), or both (lower right). C–E, Outputs of models predicting death by 28 days. Adjusted odds ratios and 95% credible intervals of effect of different antimicrobial therapies (C), predicted mortality as a function of time to antibacterial therapy (D), and volume of intravenous fluid received (E). Abbreviations: Cr, creatinine; GCS, Glasgow coma score; Hb, hemoglobin; HIV, human immunodeficiency virus; HR, hazard ratio; OR, odds ratio; PC, principal component; RR, respiratory rate; SpO₂, oxygen saturation; WCC, white cell count; Plt, platelet count.